Glycogen metabolism is an important part of glucose metabolism. In particular, glycogen metabolic disorders become a major pathological factor in certain disease states. Research shows that the regulation and control of insulin on liver glycogen metabolism is one of the key mechanisms for maintaining whole body blood glucose equilibrium, myocardial ischemia injury has definite correlations with abnormal cardiac glycogen metabolism, and abnormal brain glycogen metabolism also has some correlations with cerebral ischemic injury (Journal of China Pharmaceutical University, 2006, 37, 1).
At present, some signal conducting molecules and receptor proteins of glycogen metabolism, such as glycogen synthase kinase-3, glycogen phosphorylase, protein kinase B and glucagon receptor, etc., have become potential drug targets for treating type 2 diabetes, ischemic cardiovascular diseases, tumors, psoriasis and so on (Med. Res. Rev, 2002, 22, 373; Curr. Protein Pep. Sci., 2002, 3, 561; Cancer Res., 2006, 66, 5130; Expert Opinion Therap. Pat., 1999, 9, 701).
Among them, glycogen phosphorylase (GP) is a key enzyme in glycogen metabolism. Said enzyme can catalyze the phosphorolysis of glycogen to release glucose-1-phosphate, which is then converted into glucose-6-phosphate under the catalyzation of phosphoglucomutase. Glucose-6-phosphate is either converted into glucose for body tissues under the catalyzation of glucose-6-phosphatase, or directly involved in energy supply in anaerobic and aerobic metabolic pathways. Since the glycogen phosphorylase is a key factor in glycogen metabolism, the pharmacological inhibition of the glycogen phosphorylase might be used to treat the diseases associated with excessive glycogen degradation such as diabetes, ischemic myocardial injury, tumors and so on (Curr. Protein Pept. Sci., 2002, 3, 561; Am. J. Physiol. Heart. Girc. Physiol., 2004, 286, H177).
Moreover, hypertension and its associated pathological changes, such as atherosclerosis, hyperlipidemia and hypercholesterolemia, etc., have been all associated with elevated insulin levels. Inhibition of glycogen phosphorylase can effectively reduce insulin levels, and thus can be used in the treatment of diseases such as hypercholesterolemia, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia, etc.
In recent years, the development of novel glycogen phosphorylase inhibitors has attracted wide attention. For example, U.S. Pat. No. 6,297,269 and European Patent Application No. EP0832066 described substituted N-(indole-2-carbonyl) amides and their derivatives as glycogen phosphorylase inhibitors. U.S. Pat. No. 6,107,329 described substituted N-(indole-2-carbonyl) glycinamides and their derivatives as glycogen phosphorylase inhibitors. European Patent Application No. WO2006059163 described pyrrolopyridine-2-carboxylic acid amide derivatives as glycogen phosphorylase inhibitors.